This is an amended R01 to test the efficacy of cognitive behavioral therapy for adherence and depression (CBT-AD) in individuals with HIV and clinical depression who are in care for HIV. Clinical depression is one of the most frequently occurring (if not the most frequently occurring) and distressing conditions comorbid with HIV. Clinical depression consistently interferes with adherence and can affect medical outcome in individuals with HIV. Studies by the PI and others have shown that cognitive-behavioral interventions can be successful in improving HIV medication adherence. However, major depressive disorder may attenuate the degree to which individuals with HIV can benefit from such interventions. Despite the overwhelming evidence that depression is one of the most consistent predictors of poor adherence, interventions that incorporate treatment of depression with adherence training are lacking. Overview. Building on our prior work, this is a three-arm, randomized controlled efficacy trial of cognitive-behavioral therapy for major depressive disorder and HIV medication adherence in patients with HIV and major depressive disorder. Conceptual Model: Symptoms of major depressive disorder (e.g. low motivation, poor concentration, persistent loss of interest, sad mood, and suicidal ideation) in the context HIV infection are highly distressing and can substantially interfere with self-care behaviors necessary for managing HIV. Additionally, for individuals with major depressive disorder, attempts to improve adherence that do not address comorbid depression may be futile. We hypothesize that adding CBT for depression to adherence training will improve both mood and medication adherence, thereby promoting healthier living with HIV. Overview of Research Plan. Patients who are HIV infected and have a diagnosis of major depressive disorder will be randomized. The three arms are: (1) CBT-AD, cognitive behavioral therapy for depression and adherence which lasts 12 sessions (2) TMC a time matched comparison group that involves our previously tested intervention for adherence (Life-Steps) delivered in an initial session in conjunction with education and support provided by a therapist, 3) ETAU - Enhanced Treatment as Usual - the single-session adherence intervention. All randomized participants, regardless of arm, will have feedback sent to their provider regarding baseline study assessments and treatment as it would normally occur. Participants will be followed for one-year post-randomization. Outcomes include adherence, depression, and HIV viral load. Additionally, we will collect resource utilization and cost data to examine the cost-effectiveness of reduced depression, and potentially, better HIV outcomes. PUBLIC HEALTH RELEVANCE: Major depressive disorder is a frequently occurring, costly, distressing, interfering, and sometimes devastating disorder in individuals with HIV, and has consistently been shown to be associated with poor adherence to HIV medications. Interventions that incorporate evidenced based approaches to the treatment of depression with promotion of health behaviors are lacking for patients with medical conditions in general and HIV in particular. Following successful formative work through our NIMH R21, we propose a full-scale randomized controlled efficacy trial of cognitive behavioral therapy for adherence and depression in HIV.